1. Field of the Invention
This invention relates to 2', 4"'-O-di-O-trialkylsilyl derivatives of tylosin, 3,2',4"'-tri-O-trialkylsilyl derivatives of tylosin, 4"'-O-trialkylsilyl derivatives of tylosin, 3,4"'-di-O-trialkylsilyl derivatives of 2'-O-acyl-tylosins and 4"'-O-trialkylsilyl derivatives of 2'-O-acyl-tylosins, which are useful as intermediates for the synthesis of various tylosin derivatives (components of 16-membered macrolide antibiotics); and to processes for producing the same.
2. Description of the Prior Art
16-Membered macrolide antibiotics have excellent anti-bacterial activity and are widely used as medicines (for both humans and animals) and additives to animal feeds. Tylosin, in particular, is being produced in large quantities on a commercial scale.
However, macrolide antibiotics generally have the disadvantage of inefficient absorption and excretion when administered to living bodies. In addition, drug-resistant strains of bacteria have appeared as is usual with antibiotics in general. Under the circumstances, many chemical and biological studies are under way on the development of new tylosin derivatives having improved absorption and excretion characteristics and imparted with antibacterial potency against the drug-resistant strains.
Tylosin is a compound represented by the following formula: ##STR2##
It has been found that derivatives thereof in which the hydroxyl group at 4"-position of the disaccharide residue attached to the 5-position of tylosin has been acylated [for example, 4"-O-(4-methoxyphenylacetyl)tylosin, 4"-O-(4-acetylphenylacetyl)tylosin, 4"-O-(4-methylthiophenylacetyl)tylosin, 4"-O-(3-pyridylacetyl)tylosin and 4"-O-(4-methylsulfonylphenylacetyl)tylosin]have high antibacterial activity against the bacteria resistant to macrolide antibiotics and show improved absorption and excretion efficiency (U.S. Pat. Nos. 4612372 and 4205163).
For the chemical synthesis of these 4"-O-acyl derivatives from tylosin, a method has been adopted in which the two hydroxyl groups at 2'-and 4"'-positions are previously protected, a desired acyl group is introduced to 4"-position, and the two protective groups are removed [M. Tsuchiya et al.: J. Antibiotics, 35, 661 (1982)].
For example, tylosin is allowed to react with acetic anhydride to form 2'-0-acetyltylosin, which is acylated in dichloromethane in the presence of pyridine by a halogenated lower-alkanoyl halide, a lower-alkoxycarbonyl halide or a phenoxyacetyl halide, the corresponding 2',4"'-di-O-acyltylosin thus formed is isolated, and a desired acyl group is introduced into the 4"-position, followed by removal of the protective group (or groups) at the 4"'-and/or 2'-positions (U.S. Pat. No. 4205163). This method, however, gives 4"-O-acyl derivatives in a low yield of 10 to 30% and requires chromatography for isolation.
On the other hand, a technique has been disclosed in which 4"'-O-tert-butyldimethylsilyltylosin is prepared by treating tylosin with tertbutyldimethylchlorosilane in dimethylformamide in the presence of imidazole (U.S. Pat. No.393901).
Tylosin contains four secondary hydroxyl groups in the molecule, and the ease of acylation is in the order of 2'-, 4"'-, 4"-and 3-positions. Hence, the hydroxyl groups at 2'- and 4"'-positions must be protected when tylosin derivatives (particularly 4"-O-acyltylosin) are chemically synthesized by the above-mentioned conventional methods. The 2'hydroxyl group can be easily differentiated from the other hydroxyl groups because it can be acylated in the absence of basic catalyst due to the effect of the adjacent dimethylamino group at the 3'position. However, the succeeding acylation of 4"'-hydroxyl group for protection gives, as by-product, 2'-O-acyl protected-4", 4"'-di-O-acylprotected-tylosin because of little difference in reactivity between the 4"'- and 4"-hydroxyl groups, and hence this by-product must be removed by chromatography or the like in order to obtain pure 2'-O-acyl-protected-4"'-O-acyl-protected-tylosin. In addition, the following acylation of 4"-hydroxyl group is accompanied by acylation of the 3- hydroxyl group. Thus, the final desired product (4"-O-acyltylosin derivatives) is obtained only in a low yield.
On the other hand, selective protection of the 4"'-hydroxyl group with tert-butyldimethylsilyl group also involves several problems: the reaction requires a large excess of relatively expensive reagents, tertbutyldimethylchlorosilane and imidazole; the objective 4"'-O-tert-butyldimethylsilyl derivative has to be isolated by chromatography or other techniques because of its rather low yield; and the reaction takes a long time for completion.